Container Closure Integrity Testing - Method Development for Freeze Dryed Products Using laser based Headspace Oxygen Analysis.

The regulatory expectations introduced by USFDA in 1999, ICH Q5C and revised draft Annex-1-Eudralex volume 4 for consultation, the recent update of USP general chapters 1207.1 and 1207.2, regarding Container Closure Integrity testing (CCIT), has created a need for further development of testing methods, although there are no universally accepted testing method to test and evaluate the CCI of a Biopharmaceutical drug product. Each testing method and principle has merits and demerits. This paper will present a simple approach to be used in method validation of a CCIT method based on headspace oxygen analysis for freeze dried biopharmaceutical drug products in vials, as well as a method for testing and verifying positive control vials. The model is based on Fick's law of diffusion and empirically corrected to account for Knudsen Diffusion in the smaller defect sizes. The model takes into account storage conditions of the vials, allowing for testing of vials stored under anaerobic and near sealing pressure conditions, and different temperature conditions - as well as testing at different time points. Using this approach, based on headspace oxygen analysis, the minimum timeframe for leak detection is dependent on the volume of the object tested, but standard vial sizes have shown that leak sizes of 0.2 µm can be detected within hours of vial stoppering with the model developed. CCI testing by headspace oxygen analysis using this approach can be done quickly and non-destructive. This method can prove its effectiveness in demonstration of a protective critical barrier (CCI) for a biopharmaceutical drug product during real time situations of manufacturing, transportation, registered storage conditions etc. (Life cycle approach).